THEN Whitehead Institute 2009 ANNUAL REPORT “ I’m constantly amazed now at how much of development seems to be about nuance…We have made enormous progress in describing many of the genes required, but the magnitude of the challenge to get the real picture of what’s actually occurring, and the subtleties involved, is something I didn’t NOWappreciate 20 years ago. ” CONTENTS 1 OUR FUTURE IS NOW 2 SCIENTIFIC ACHIEVEMENT 11 PRINCIPAL INVESTIGATORS 40 WHITEHEAD FELLOWS 42 COMMUNITY EVOLUTION 44 HONOR ROLL OF DONORS 48 FINANCIAL SUMMARY 49 LEADERSHIP cover quote Commentary from Whitehead Institute Member Hazel Sive contemplating the 2009 Annual Report theme, “What I thought then…What I know now.” Her colleagues’ perspectives on the same subject may be found beginning on page 11 of this report. background image During endocytosis, clathrin-lined pockets of a cell’s membrane engulf exterior molecules, creating membrane-bound bubbles that shuttle the molecules into the cell’s interior. Whitehead Special Fellow Defne Yarar is studying the activity of a clathrin protein shown here (stained green in this monkey kidney cell) and other molecules that associate with it, including one known as SH3D19 (stained blue). credits director and editor MATT FEARER associate editor NICOLE GIESE editorial assistant CEAL CAPISTRANO design HECHT DESIGN photography CHRIS SANCHEZ IMAGES: page 3 Reproduced with permission. From Dickinson AJ, Sive HL, Development, 2009, 136(7):1071-81. page 4 Reprinted from Cell,136(5), Soldner F, Hockemeyer D, Beard C, Gao Q, Bell GW, Cook EG, Hargus G, Blak A, Cooper O, Mitalipova M, Isacson O, Jaenisch R, “Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors,” 964-77, 2009, with permission from Elsevier. page 5 Reprinted from Cancer Cell, 15(2), Guertin DA, Stevens DM, Saitoh M, Kinkel S, Crosby K, Sheen JH, Mullholland DJ, Magnuson MA, Wu H, Sabatini DM, “mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice,” 148-59, 2009, with permission from Elsevier. page 6 From “Haploid genetic screens in human cells identify host factors used by pathogens,” Carette JE, Guimaraes CP, Varadarajan M, Park AS, Wuethrich I, Godarova A, Kotecki M, Cochran BH, Spooner E, Ploegh HL, Brummelkamp TR. Science. 2009 Nov 27;326(5957):1231-5. Reprinted with permission from AAAS. page 8 Stacie Bumgarner Our Future Is Now Breaking news on the opening and became a postdoctoral research associate with our page of a document as tradition- neighbor and former Whitehead Member Eric Lander at ally retrospective as an annual Broad Institute. Piyush is studying the genes and signaling report may seem a tad unortho- networks that control both normal epithelial stem cells dox. However, shortly before this and cancer stem cells. His research will add to Whitehead’s publication reached the presses, already considerable contributions in this arena. I was able to conclude a process In addition to these faculty hires, our Whitehead Fellows whose outcome is so fundamental program, which allows a handful of particularly promising, to the continued success of newly minted scientists to establish labs and pursue their Whitehead Institute that I can think of no medium more own research agendas over a four- or five-year period, has appropriate for its announcement. attracted a new recruit. Yaniv Erlich, who graduated from As supporters and friends of the Institute well know, my top Tel-Aviv University with honors degrees in biology and priority as Director has been faculty recruitment. Last year in psychology, recently completed his doctorate at Watson this space, I described a Board-approved plan for new faculty School of Biological Sciences at Cold Spring Harbor hires. Now, after an exhaustive search and thorough vetting Laboratory. Yaniv will focus on high-throughput personal of a remarkably deep pool of candidates, I’m delighted to genomics during his time here. inform you that two exceptionally creative young scientists The excitement generated by the launching of these three will soon join our ranks. You’ll learn much more about these careers aligns perfectly with a theme of this report: “What talented individuals in the months and years to come, but I thought then…What I know now.” Within these pages, our allow me to introduce them briefly. Members recount conceptual shifts and occasional surprises Plant biologist Mary Gehring comes here after completing her that can alter a continuum of research. We can’t predict postdoc at Fred Hutchinson Cancer Center in Seattle. Mary what those might be for Mary, Piyush, and Yaniv, but it’s earned her PhD at the University of California, Berkeley after thrilling to know they’re about to find out for themselves. receiving a BA in biology with highest honors from Williams In closing, I should note that all three newcomers had College. Mary’s arrival heralds a welcome return to our roots multiple suitors vying for their services. That they have in plant biology. She’ll fill our seventh-floor greenhouse with chosen Whitehead Institute is a tribute to our faculty, staff, Arabidopsis thaliana, which she’ll use as a model in which to friends, and supporters, whose passion and dedication make study epigenetic reprogramming. Her work will provide valu- ours such a uniquely appealing culture. And for that, I am able insights into this and other developmental processes not extraordinarily grateful. only in plants but in mammals as well, and will complement research occurring in several other Whitehead labs. Mary’s cross-country journey to Cambridge is considerably Sincerely, longer than that taken by cancer researcher Piyush Gupta. An honors graduate of the University of Chicago, Piyush earned his PhD under the tutelage of our own Bob Weinberg David C. Page 1 Scientific Achievement The productivity of Whitehead laboratories continued apace in 2009. High-impact research findings were published throughout the year, adding to a burgeoning base of knowledge in such areas as genetics, genomics, molecular biology, developmental biology, immunology, cancer research, and stem cell science. Accordingly, many of those behind work of this significance were honored for their contributions. 2 In the Xenopus frog embryo, opening the primary mouth (bracketed in the image at left) depends on the dissolution of the basement membrane (stained green). If the Wnt signaling pathway is interrupted, the basement membrane remains intact (right image). Organisms develop—as they’re ‘Wnt’ to do their subsequent protein production (which then allows Wnt CELL SIGNALINGsignaling to occur) leaves the basement membrane intact and The Wnt signaling pathway is a workhorse in nearly all multi-cellular organisms. This potent network of genes and prevents the formation of the primary mouth. The researchers related proteins mediates multiple patterns of cell-to-cell thus concluded that Wnt inhibition is essential in forming the communication, thereby regulating a host of core biological mouth opening and may play a role in other developmental processes, ranging from embryogenesis, to morphological processes involving basement membrane remodeling. development, to carcinogenesis. As fundamental as the Meanwhile, in the lab of Member Peter Reddien, scientists pathway is, a comprehensive accounting of its components, intent on understanding what’s known as the head-to-tail their functions, and subsequent effects remains a work in polarity decision were discovering that Wnt signaling is progress. Research in Whitehead labs continues to add to pivotal in determining whether a planarian flat worm regen- the Wnt story, recently implicating the pathway in two more erates the proper body part in its proper place. Researchers pivotal developmental events. found that blocking the expression of a Wnt-related gene Scientists in the lab of Member Hazel Sive found Wnt (wntP-1) in an animal whose tail had been removed prompted signaling at work in forming the so-called primary mouth growth of a head in place of a tail—that is, a two-headed in embryos of the frog Xenopus. Formation of the primary planarian. During their work, the scientists noted that mouth—the first opening between the outside of the increased Wnt signaling triggers tail regeneration. From this embryo and the intestine—is a critical developmental step research, Reddien and his colleagues have concluded that requiring the dissolution of a protein sheet known as the low levels of Wnt signaling, which are normally observed at basement membrane. Researchers identified two genes that the anterior pole of the animal, promote head growth, while become highly expressed in the region during the formation higher levels of Wnt signaling are typically a posterior event, of the primary mouth, noting that the proteins these genes leading to tail growth. It now appears this signaling pattern code for are known to interrupt Wnt signaling. Blocking guides development of the head-to-tail axis across a vast the expression of these genes (frzb-1 and crescent) and number of species. 3 Parkinson’s disease (PD) causes neurodegeneration, leading to insufficient levels of the neurotransmitter dopamine. Via cellular reprogramming, the Jaenisch lab derived from the skin cells of PD patients neurons capable of producing dopamine (stained green in the image above) and an enzyme found only in dopaminergic neurons (stained red). When the program needs editing sequences called loxP, which respond to the Cre enzyme. STEM CELLSPost-insertion, the team introduced Cre into the cells, The discovery of cellular reprogramming brought with it enough hope to obscure the fact that, though extraordinary, triggering a reaction at the loxP sites that caused a deletion the process was far from perfect. The successful reversion of all four of the target genes. Beyond successful removal of of fully matured cells to an embryonic stem cell-like state— the genes, expression analysis of these induced pluripotent from which they could have the potential to become any stem cells revealed their genomes to be virtually identical cell type in the body—was practically the stuff of science to those of the PD patients from whom the original skin fiction.